Noise-induced hearing loss is an incurable, often progressive disease that impairs the quality of life. This project, using animal models, has provided evidence for degeneration of synaptic endings in the brain, besides loss of cochlear hair cells, as a major factor in this disease. This research offers preliminary data that the balance between excitatory and inhibitory endings in the cochlear nucleus shifts over time towards excitation and hyperactivity. The overall hypothesis is that these shifts provide a structural basis for tinnitus and hyperacusis after noise exposure. The project will characterize the degenerative process, at the cell and molecular levels, and trace changes in synaptic organization, including the exciting discovery that new synapses can form after the initial damage. The experiments aim to uncover factors that protect synapses or promote recovery after noise. Light and electron microscopy are used to examine damage in the cochlear nucleus of mice. Changes in the proportion of excitatory and inhibitory endings will be quantitated over 1-120 days after noise exposure. Synaptic vesicle histochemistry with light microscopy will show the numbers and locations of endings. Electron microscopy will show the proportion of endings with excitatory or inhibitory cytology using stereological approaches to test the hypothesis. Immunocytochemistry by light and electron microscopy will identify molecules underlying these changes. Transmitter-related molecules, including excitatory and inhibitory receptors and transporters, will be localized to specific types of neurons and synapses and tracked over the survival period. These data will pinpoint where and when in the cochlear nucleus an excitotoxic process may occur in cells. Neurotrophic factors and receptors will be identified and localized to indicate a role for trophic mechanisms. The role of fibroblast growth factor will be evaluated in a transgenic mouse that over expresses this factor. The hypothesis is that this factor protects against damage, and neurotrophins promote new growth of synapses. The results should lead to proposals for new therapies.